The present invention relates to compositions including modified human transcription factors, recombinant adeno-associated viral vectors (AAVs) comprising modified human transcription factors, and methods for treatment of muscular defects.
Duchenne's muscular dystrophy (DMD) is a severe X-linked muscle degenerative disease caused by the absence of the cytoskeletal protein dystrophin. The dystrophin protein provides stability to the sarcolemma (i.e., the cell membrane of muscle cells) by linking the intracellular cytoskeletal network to the extracellular matrix. In the absence of dystrophin, muscle contraction mechanically stresses the cell membrane, inducing progressive damage to the myofibers. Initially, skeletal muscles are predominantly affected; however, as the disease progresses, the damage extends to cardiac muscle and death is usually caused by cardiac failure. DMD is one of the most common genetic diseases, affecting an estimated 1 out of every 3,600 male births each year. DMD is a debilitating disease that progressively worsens over the short (approximately 25 year) lifespan of those affected. Unfortunately, despite years of research, there are no curative treatments for muscular dystrophies including DMD. Current therapies are limited to managing symptoms.
The design of new therapies for DMD or related dystrophinopathies has been focused on functionally rescuing the absent or defective dystrophin protein. Accordingly, there exists a need for compositions capable of increasing utrophin expression which are less immunogenic and more therapeutically efficacious.